chr19-41352717-G-A

Position:

• chr19-41352717-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_Moderate PM1 PM2 PP5_Moderate

The NM_000660.7(TGFB1):​c.328C>T​(p.Arg110Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TGFB1 NM_000660.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 1.37

Genes affected

TGFB1 (HGNC:11766): (transforming growth factor beta 1) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGFB family members. This encoded protein regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors including interferon gamma and tumor necrosis factor alpha. This gene is frequently upregulated in tumor cells, and mutations in this gene result in Camurati-Engelmann disease. [provided by RefSeq, Aug 2016]

TMEM91 (HGNC:32393): (transmembrane protein 91) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle and membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PS1: Transcript NM_000660.7 (TGFB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a chain Latency-associated peptide (size 248) in uniprot entity TGFB1_HUMAN there are 21 pathogenic changes around while only 2 benign (91%) in NM_000660.7
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-41352717-G-A is Pathogenic according to our data. Variant chr19-41352717-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488345.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFB1	NM_000660.7	c.328C>T	p.Arg110Cys	missense_variant	1/7	ENST00000221930.6
TGFB1	XM_011527242.3	c.328C>T	p.Arg110Cys	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFB1	ENST00000221930.6	c.328C>T	p.Arg110Cys	missense_variant	1/7	1	NM_000660.7	P1
TMEM91	ENST00000539627.5	c.-30+1515G>A		intron_variant		1
TGFB1	ENST00000600196.2	c.328C>T	p.Arg110Cys	missense_variant	1/6	5
TGFB1	ENST00000677934.1	c.328C>T	p.Arg110Cys	missense_variant	1/5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Inflammatory bowel disease, immunodeficiency, and encephalopathy Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 04, 2018	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Feb 27, 2019	This variant is interpreted as a Likely pathogenic for Inflammatory bowel disease, immunodeficiency, and encephalopathy, autosomal recessive. The following ACMG Tag(s) were applied: PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 : Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Moderate : PS3 downgraded in strength to Moderate (PMID:29483653). PM3 : For recessive disorders, detected in trans with a pathogenic variant (PMID:29483653). -

Encephalopathy;C4749850:Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

research

Klein lab, Ludwig-Maximilians-University

Jan 01, 2017

Variant is associated with primary immunodeficiency, inflammatory bowel disease and encephalopathy. Variant was found in compound heterozygosity with another variant in TGFB1 (c.1159T>C). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Benign	0.12
Eigen_PC	Benign	-0.0063
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.51	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.38
MutPred		0.80		Gain of catalytic residue at E107 (P = 0.0727);
MVP		0.79
MPC		1.9
ClinPred		1.0	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555755242; hg19: chr19-41858622;